Stent Drug Delivery System

ABSTRACT

Expandable intraluminal stents are provided as well their method of manufacture. These stents are made of metal, the metal characterized by a desired porosity, with a drug compressed into the pores of the stent. The stents are formed by subjecting one or more powdered metals in a die cavity to a pressure treatment followed by a heat treatment. The metal may be cast directly in a stent-like form or cast into sheets or tubes from which the inventive stents are produced. The so-formed porous metal stent is then loaded with one or more drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.08/940,696 filed Sep. 30, 1997, the contents of which are incorporatedherein in their entirety by reference.

BACKGROUND OF THE INVENTION

This invention relates to stents for maintaining the patency of bodypassages. Additionally, the stents may serve as drug delivery vehicles.The invention has particular application to stenting in blood vessels ofthe human body and will be described with reference thereto However, ina broader sense it relates to stenting in any body passage, includingsuch passages as the gastrointestinal tract, urethral and ureteraltracts, bronchial and esophageal tracts The invention also hasparticular reference to stents comprising compounds useful for thetreatment and prevention of restenosis and also will find application indilating and maintaining the patency of various body passages such asureters and the like.

SUMMARY OF THE INVENTION

In accordance with the present invention, a porous stent made from apowdered metal or polymeric material is disclosed. The inventive stentis an expandable intraluminal stent comprising a main body portionhaving a first end, a second end and a flow passage definedtherethrough, the main body portion being sized for intraluminalplacement within a body passage and subsequent expansion forimplantation. The main body portion of the stent of the presentinvention is further characterized in that it is formed at least in partof at least one porous material, the porous material having been formedfrom a powdered metal or polymeric material.

In another embodiment of the present invention, a drug is containedwithin the pores of the stent for delivery to the body.

In another embodiment of the present invention, the stent may be coatedwith a drug.

In another embodiment of the present invention, the stent is comprisedof at least two porous metals.

The present invention is also directed to a method for making a porousexpandable intraluminal stent comprising the steps of providing apowdered material, subjecting the powdered material to high pressure toform a compact, sintering the compact to form a final porous materialand forming a stent from the porous material. In another embodiment ofthe above-mentioned inventive method, at least one drug is loaded intothe pores of the stent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 a is a perspective view of one embodiment of a stent according tothe present invention.

FIG. 1 b is an enlargement of a portion of FIG. 1 a showing poses on thesurface of the metal.

FIG. 2 is a sectional view of another embodiment of a stent inaccordance with this invention.

FIG. 3 is a perspective view of another embodiment of a stent accordingto the present invention.

FIG. 4 a is a plan view development of the inventive stent in sheet formprior to rolling

FIG. 4 b is a sectional view of another embodiment of a stent accordingto the present invention

FIG. 5 is a perspective view of yet another embodiment of a stentaccording to this invention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EXEMPLARY EMBODIMENTS

The present invention relates to a porous stent made from a powderedmaterial such as powdered metal or polymer for maintaining the patencyof body passages Stents to which the present invention relates may beeither balloon expandable or self-expanding as well as springy in form.For example, self-expanding stents are known which are braided, woven ormesh-like in structure, although many other types of self-expandingstents including solid stents are also known Such stents have memorycharacteristics and, if distorted in length and/or diameter by externalforces, they will return or tend to return to a preformed configurationupon the release of external forces. This expansion may be due to thenatural springiness of the stent, for instance with a rolled up sheetstent, or as a result of a phase transition occurring in the stentmaterial. Balloon expandable stents may be expanded by the applicationof a suitable amount of force to the stent.

The stents of the present invention may be used to deliver drugs to adesired bodily location. As used in this application, the term “drug”denotes any compound which has a desired pharmacologic effect, or whichis used for diagnostic purposes. Useful drugs, in the context of thepresent invention include, but are not limited to angiogenic drugs,smooth muscle cell inhibitors, collagen inhibitors, vasodilators,anti-platelet substances, anti-thrombotic substances, anti-coagulants,cholesterol reducing agents and combinations thereof. The drugs mayinclude radiochemicals to irradiate and/or prohibit tissue growth or topermit diagnostic imaging of a site.

The porous stent may be used as a drug-delivery system to, for example,prevent restenosis The drugs may include radiochemicals to irradiate andprohibit tissue growth. Angioplasty and stent deployment may causeinjury of the endothelial cell layer of blood vessels, causing smoothmuscle cell proliferation, leading to restenosis. To control smoothmuscle cell growth endothelialization of cells on the inner wall surfaceof vessels will prevent or prohibit the smooth muscle growth. To promoteendothelialization human growth factors may be included in the outerlayer and delivered.

The stent of the present invention may be formed of any bio-compatiblepowdered metals such as stainless steel. Powdered metals typically areavailable in powder sizes as small as 40 microns or less While powderedmetals of any powder size may be used in forming the stents of thepresent invention, preferably powders 40 microns or less will be used informing the porous metal stout of the present invention. Morepreferably, powdered metals ranging in size from 6 to 12 microns will beused Especially desirable are powders with good flow properties so thatthe particles may be dispensed easily into a die cavity for metalprocessing. Other suitable metals include, but are not limited to,spring steel, nitinol and titanium as well as any other biocompatiblemetal which may become available in powdered form in the future.Suitable metals do not produce toxic reactions or act as carcinogens.The stent of the present invention may also be formed of bio-compatiblepowdered polymeric materials such as PTFE

The stents of the present invention may also be prepared with differentmean pore sizes. Pore size is an important parameter in that certainmacromolecular drugs may be excluded from use where the pore size isvery small. The pore size may also play a role in determining the extentof cellular infiltration or tissue ingrowth during implantation of thestent. While cellular ingrowth is sometimes desirable, it can also leadto complications such as infection and difficulty in removing the stent.Stents with a mean pore size of greater than about 10 microns can allowinfiltration of cellular sized biomaterials; stents with mean pore sizesin the range of 1-10 microns may accommodate infiltration of some of theabove bio-materials. Stents with pore sizes less than about 1 micronwill not generally accommodate infiltration of any of the abovebiomaterials but can accommodate infiltration of macromolecular andsmall biomaterials. Thus, the pore size of the stent may be varied tofoster or inhibit cellular infiltration and/or tissue ingrowth. Ofcourse, the pore size may also be varied to facilitate delivery of drugsof different molecular sizes.

The material processing proceeds with a pressure treatment step in whichthe powdered material in a die cavity is subjected to pressures of up totwenty tons or more At such high pressures, the powder begins tointerlock, forming a compact with pockets of air remaining in the metal.The pressure treatment step usually proceeds at room temperaturealthough warm or hot pressing may be used. Other techniques to form thecompact, as known in the art, may be substituted for the pressuretreatment step. The die cavity used in this step may be a stent diecavity to allow for direct casting of the stent or alternatively, may befor some other form such as a tube or a sheet. Following the pressuretreatment step, the compact has sufficient strength to allow for routinehandling without breakage.

After ejection from the die, the compact is sintered to form a coherentmetal or polymer mass in the shape of the die. Alternatively, thepressure treatment step can be eliminated and the processing limited toa sintering in which the metal of polymer powder is heated in a dieresulting in a low density, highly porous compound Although thesintering step may actually partially melt the metal or polymer as inliquid-phase sintering, in the preferred embodiment, the sintering stepdoes not melt the metal or polymer as the temperature is maintainedbelow the melting point of elemental metal or any alloys that haveformed or the polymer melting point. The sintered metal or polymer willexhibit a porosity ranging from less than 10 percent to about 80 percentof the total volume. The percentage porosity is a measure of the voidspace within the metal.

Following sintering, the now porous metal or polymer may be formed intoa stent, if it has not been so-formed already. Any known process in theart may be used including laser cutting and braiding of porous metalstrands. FIGS. 1 a and 1 b illustrate one such stent 10, with pores 14formed by laser cutting apertures 18 in a sheet of porous metal. FIG. 2illustrates a stent 20 which is composed of a number of interconnectedmembers 22, the members and interconnections 24 made of a metalcontaining pores 26. A braided stent may be formed of a series ofstrands arranged in a crossing configuration which may be woven, braidedor the like. The stands of porous metal or polymer can be deformed so toprovide a reduced diameter of the stent which facilitates its deliveryto the targeted portion of a vessel or other passageway and oncedisposed at the target portion the stent can then be allowed to expandto its preformed configuration and larger diameter.

The stents of the present invention may be prepared in a range ofporosities allowing for the production of stents with differing drugdelivery characteristics. The porosity may be between twenty and eightypercent of the total volume and more suitably between forty and sixtypercent of the volume.

The stent may be impregnated with one or more drugs by any known processin the art including high pressure loading in which the stent is placedin a bath of the desired drug or drugs and subjected to high pressureor, alternatively, subjected to a vacuum. The drug may be carried in avolatile or non-volatile solution. In the case of a volatile solution,following loading of the drug, the volatile carrier solution may bevolatilized. In the case of the vacuum, the air in the pores of themetal stent is evacuated and replaced by the drug-containing solution

In accordance with the present invention, the stent may further becoated with one or more layers of one or more drugs to allow for longerterm drug elution optionally employing a number of different drugs overtime. As such, the drug in the pores would not be eluted until thecoating of drug has been absorbed, thereby allowing for longer term drugtreatment than would be available from the coated metal alone.

FIG. 3 shows a coil stent 30 in which the porous metal stent 30 furthercomprises such a coating 32 (the pores have been omitted for clarity).

The inventive stent may also be formed from a rolled up flat sheetcomprised of a porous metal or polymer as shown in FIG. 4 a. The sheet35 contains a plurality of apertures 36 and pores 38 as well as tabs 37.The tabs are inserted into the holes 36 a-c when the stent is rolled, asshown in FIG. 4 b. The stent may be rolled tightly for delivery andimplantation and be self-expandable to the extent that it tends tounroll. The stent may further be laminated with a layer of drug over theporous surface of the stent. Otherwise, it may simply be expanded byindependent expansion means such as a balloon catheter positioned insidethe stent as is already known in the art.

Another embodiment of the invention contemplates the fabrication of anystent design per se taken from the prior art, the stent prepared from aporous metal or polymer, the pores of the metal or polymer including oneor more drugs.

Another embodiment of the invention is an expandable intraluminal stentcomprising a main body portion having a first end, a second end and aflow passage defined therethough, the main body portion being sized forintraluminal placement within a body passage and subsequent expansionfor implantation, the main body portion being further characterized inthat it is formed at least in part of at least two metals, the twometals comprising a first porous metal characterized by a first porosityand mean pore size and a second porous metal characterized by a secondporosity and mean pore size FIG. 5 depicts one such stent, 40, the firstmetal 42 containing first pores 44 therein and the second metal 46containing second pores 48 therein.

In the above embodiment, one drug may be loaded into the pores of thefirst porous metal and a second drug loaded into the pores of the secondporous metal. Alternatively, the same drug can be loaded into both thefirst and second porous metals

The present invention is also directed to a method for making a porousmetal, expandable intraluminal stent comprising the steps of providing apowdered metal or polymeric material, subjecting the powder to highpressure to form a compact, sintering the compact to form a final porousmetal or polymer, forming a stent from the porous metal and, optionally,loading at least one drug into the pores. The drug(s) may be loaded intothe pores by placing the stent in a liquid bath comprising the at leastone drug at high pressure, by placing the stent in a liquid bath withina chamber, the liquid bath comprising the drug(s), and reducing thepressure within the chamber below ambient pressure or by any othermethod known in the art.

In yet another embodiment, the invention is directed to a method ofmaking an expandable intraluminal stent of varying porosity comprisingthe steps of providing two or more metal and/or polymeric powders in adie, subjecting the two or more powders to high pressure to form acompact, sintering the compact to form a final porous metal or polymerof varying porosity, forming a stent from the porous metal or polymerand, optionally, loading at least one drug into the pores. The two ormore powdered metals and/or polymers can comprise at least two differentmetals and/or polymers or can comprise one metal or polymer, the onemetal or polymer provided in at least two different average particlesizes or can comprise several different metals or polymers provided inseveral different average particle sizes. In such a way, the porosity ofthe stent in different regions of the stent can be tailored by formingthe stent of several different powdered metals or polymers comprising acombination of different elemental metals or alloys or polymers inpowdered form, of using the same elemental metal, alloy or polymer butproviding it in several powders of different average particle size or bysome combination of different metals and/or polymers and same metalsand/or polymers of different particle size.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiments,it is to be under stood that the invention is not to be limited to thedisclosed embodiments but, on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

The above Examples and disclosure are intended to be illustrative andnot exhaustive. These examples and description will suggest manyvariations and alternatives to one of ordinary skill in this art Allthese alternatives and variations are intended to be included within thescope of the attached claims. Those familiar with the art may recognizeother equivalents to the specific embodiments described herein whichequivalents are also intended to be encompassed by the claims attachedhereto.

1-22. (canceled)
 23. An expandable intraluminal stent comprising: a mainbody portion having a first end, a second end and a flow passage definedtherethrough, the main body portion being sized for intraluminalplacement within a body passage and subsequent expansion forimplantation, the stent further comprising at least two separate regionsarranged along the length of the main body portion, the first regioncomprising a first powdered material having first pores within, thefirst material characterized by a first porosity and a first pore size,the second region comprising a second powdered material having secondpores within, the second material characterized by a second porosity anda second pore size.
 24. The stent of claim 23, wherein the firstpowdered material and the second powdered material are characterized bydifferent average particle size.
 25. The stent of claim 23, wherein thefirst powered material comprises a first polymer, and wherein the secondpowdered material comprises a second polymer.
 26. The stent of claim 25,wherein the first powdered material comprises the first polymer and afirst metal, and wherein the second powdered material comprises thesecond polymer and a second metal.
 27. The stent of claim 26, whereinthe first metal and the second metal are characterized by differentaverage particle size.
 28. The stent of claim 26, wherein at least oneof the first and second regions has a porosity of twenty percent toeighty percent by volume.
 29. The stent of claim 26, wherein at leastone of the first and second regions has a porosity of between fortypercent and sixty percent by volume.
 30. The stent of claim 26, whereinthe first metal is different than the second metal.
 31. The stent ofclaim 26, wherein the first polymer is different than the secondpolymer.
 32. The stent of claim 26, wherein the pores in the firstmaterial and the second material contain at least one drug.
 33. Thestent of claim 32, wherein the first pores contain a first drug and thesecond pores contain a second drug, the first drug being different fromthe second drug.
 34. The stent of claim 32, wherein the stent is coatedwith one or more layers of one or more drug containing materials. 35.The stent of claim 32, wherein the at least one drug is selected fromthe group consisting of smooth muscle cell inhibitors, collageninhibitors, vasodilators, anti-platelet substances, anti-thromboticsubstances, anti-coagulants, cholesterol reducing agents, angiogenicsand combinations thereof.
 36. A method of forming a stent comprising thesteps of: providing a first powdered polymer; providing a secondpowdered polymer, the first powdered polymer and second powdered polymerhaving different compositions or different physical properties or both;treating the first and second powdered polymer to form a stent preformhaving a length, the stent preform including a first region comprisingthe first powdered polymer and a second region comprising the secondpowdered polymer, the first region displaced along the length of thestent preform from the second region; and forming a stent from the stentpreform.
 37. The method of claim 36, wherein the step of providing afirst powdered polymer further includes providing a first powderedmetal, and wherein the step of providing a second powdered polymerfurther includes providing a second powdered metal, the first powderedmetal and second powdered metal having different compositions ordifferent physical properties or both.
 38. The method of claim 37,wherein the treating step includes subjecting the first powdered metal,the first powdered polymer, the second powdered metal, and the secondpowdered polymer to high pressure to form the stent preform.
 39. Themethod of claim 37, wherein the treating step includes subjecting thefirst powdered metal, the first powdered polymer, the second powderedmetal, and the second powdered polymer to high pressure to form acompact, and sintering the compact to form the stent preform.
 40. Themethod of claim 37, wherein the treating step includes sintering thefirst powdered metal, the first powdered polymer, the second powderedmetal, and the second powdered polymer to form the stent preform. 41.The method of claim 37, wherein the first powdered polymer and thesecond powdered polymer are characterized by different average particlesize.
 42. The method of claim 37, wherein the first powdered metal andthe second powdered metal are characterized by different averageparticle size.
 43. The method of claim 37, wherein the first powderedmetal and the second powdered metal are of different compositions 44.The method of claim 37, wherein the first powdered polymer and thesecond powdered polymer are of different compositions.
 45. The method ofclaim 37, further comprising the step of filling the pores in the firstmaterial and the second material with at least one drug.
 46. The methodof claim 45, wherein the step of filling the pores in the first materialand the second material with at least one drug further comprises fillingthe pores in the first material with a first drug and filling the poresin the second material with a second drug, the first drug beingdifferent from the second drug.
 47. The method of claim 45, furthercomprising the step of coating the stent with one or more layers of oneor more drug containing materials